Neonatal cardiac arrest is an infrequent, high-stakes event that requires optimal response for maximal survival and neurologic outcome. Key cardiopulmonary resuscitation (CPR) skills such as chest compressions are based on arbitrary recommendations (a depth of 1/3 the anteroposterior diameter) that contribute to difficulty in mastery. The development of a novel CPR technique based on a physiologic response that provides real-time, continuous feedback about the effectiveness of CPR efforts would be a major contribution to neonatal resuscitation. Immediate, physiology-based, feedback allows the rescuer to adjust the rate and depth of compressions to maximize the physiologic response despite factors such as the victim's age or size or the cause or duration of arrest. We have developed a novel technique using end-tidal carbon dioxide (ETCO2)- directed CPR in a preclinical pediatric model (cardiac-induced etiology via ventricular fibrillation) of cardiac arest that produces survival and defibrillation rates equivalent to those of optimal standard pediatric CPR. We propose to use a preclinical neonatal model (respiratory-induced etiology via asphyxia) of cardiac arrest in piglets to compare the use of ETCO2-directed chest compressions to optimized-standard neonatal basic life support (BLS). It is important to test ETCO2-directed CPR in a respiratory-induced arrest, as the continued cardiac output without ventilation during asphyxia will produce higher CO2 levels than the cardiac-induced arrest in which cardiac output stops before ventilation. This increase in the initial CO2 burden may have an impact on the effectiveness of ETCO2 levels to direct chest compressions in comparison to optimized-standard neonatal CPR. We also propose to study the effectiveness of ETCO2-directed CPR in the setting of increased levels of preceding respiratory failure to determine the effect of respiratory failure prior to asphyxia on both methods of CPR. This study will help to answer questions about the usefulness of this novel CPR technique in arrest scenarios typical for neonatal resuscitation. Finally, we will study the effect of asphyxia duration on the usefulness of both methods of CPR. Preliminary data appear to indicate that physiology-based CPR may be more useful than standard CPR when injury is severe. All three studies include periods of BLS and advanced life support (ALS) to enable us to determine the impact of epinephrine administration on this novel method of CPR. The demonstration that ETCO2-directed chest compressions are at least as effective as optimal standard neonatal BLS and ALS will serve as the basis for clinical studies of ETCO2-directed chest compressions and further preclinical studies of other physiology-based CPR applications. Showing that this novel physiology- based technique of ETCO2-directed CPR is effective in neonatal arrest scenarios would allow rescuers to focus on maintaining optimal response to compressions rather than on arbitrary parameters that frequently result in inadequate performance.